Article information
En los últimos años, gracias en parte a la utilización de las modernas técnicas de análisis diferencial de la expresión génica, se han identificado potenciales dianas terapéuticas para la arteriosclerosis. Algunas de ellas son factores de transcripción que regulan vías metabólicas en el hígado. De este tipo son los receptores nucleares LXR (liver X receptor) y FXR (farnesol X receptor), aunque no sólo actúan en el hígado, sino que también están presentes en las células vasculares y en los monocitos/macrófagos donde regulan mecanismos clave para la aterogénesis. Estos y otros receptores nucleares que se han identificado recientemente en la pared vascular constituyen una prometedora área de investigación, al tratarse de factores de transcripción implicados en muchos de los procesos asociados a la aterogénesis y porque, al ser activados por ligandos, son dianas ideales para su modulación farmacológica.
Palabras clave:
Arteriosclerosis Receptores nucleares
LXR
FXR
Dianas terapéuticas
In the last few years, partly due to the use of modern techniques for differential analysis of gene expression, potential therapeutic targets for arteriosclerosis have been identified. Some of these are transcription factors that regulate metabolic pathways in the liver. Among this type are the nuclear receptors LXR (Liver X receptor) and FXR (Farnesol X receptor), although these nuclear receptors not only act in the liver but are also present in vascular cells and in monocytes/macrophages where they regulate key mechanisms for atherogenesis. These and other nuclear receptors that have recently been identified in the vascular wall constitute a promising field of investigation, as they are involved in many of the processes associated with atherogenesis. Furthermore, because they are activated by ligands, they are ideal targets for its pharmacological modification.
Key words:
Arteriosclerosis
Nuclear receptors
LXR
FXR
Therapeutic targets
Full text is only aviable in PDF
Bibliografía
[1.]
R. Mukherjee.
PPARs: versatile targets for future therapy for obesity, diabetes and cardiovascular diseases.
Drug News Perspect, 15 (2002), pp. 261-267
[3.]
A.J. Lusis.
Atherosclerosis.
Nature, 407 (2000), pp. 233-241
[4.]
D. Bishop-Bailey.
FXR as a novel therapeutic target for vascular disease.
Drug News Perspect, 17 (2004), pp. 499-504
[5.]
M. Makishima.
Nuclear receptors as targets for drug development: regulation of cholesterol and bile acid metabolism by nuclear receptors.
J Pharmacol Sci, 97 (2005), pp. 177-183
[6.]
P. Tontonoz, D.J. Mangelsdorf.
Liver X receptor signaling pathways in cardiovascular disease.
Mol Endocrinol, 17 (2003), pp. 985-993
[7.]
A. Chawla, J.J. Repa, R.M. Evans, D.J. Mangelsdorf.
Nuclear receptors and lipid physiology: opening the X-files.
Science, 294 (2001), pp. 1866-1870
[8.]
J. Martínez-González, L. Badimón.
The NR4A subfamily of nuclear receptors: new early genes regulated by growth factors in vascular cells.
Cardiovasc Res, 65 (2005), pp. 609-618
[9.]
G.A. Francis, E. Fayard, F. Picard, J. Auwerx.
Nuclear receptors and the control of metabolism.
Annu Rev Physiol, 65 (2003), pp. 261-311
[10.]
T.T. Lu, J.J. Repa, D.J. Mangelsdorf.
Orphan nuclear receptors as elixirs and FiXeRs of sterol metabolism.
J Biol Chem, 276 (2001), pp. 37735-37738
[11.]
J.J. Repa, S.D. Turley, J.A. Lobaccaro, J. Medina, L. Li, K. Lustig, et al.
Regulation of absortion and ABC1-mediated efflux of cholesterol by RXR heterodimers.
Science, 389 (2000), pp. 1524-1529
[12.]
K.E. Berge, H. Tian, G.A. Graf, L. Yu, N.V. Grishin, J. Schultz, et al.
Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.
Science, 290 (2000), pp. 1771-1775
[13.]
A. Venkateswaran, J.J. Repa, J.M. Lobaccaro, A. Bronson, D.J. Mangelsdorf, P.A. Edwards.
Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols.
J Biol Chem, 275 (2000), pp. 14700-14707
[14.]
Y. Luo, A.R. Tall.
Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element.
J Clin Invest, 105 (2000), pp. 513-520
[15.]
G. Cao, T.P. Beyer, X.P. Yang, R.J. Schmidt, Y. Zhang, W.R. Bensch, et al.
Phospholipid transfer protein is regulated by liver X receptors in vivo.
J Biol Chem, 277 (2002), pp. 39561-39565
[16.]
S.B. Joseph, B.A. Laffitte, P.H. Patel, M.A. Watson, K.E. Matsukuma, R. Walczak, et al.
Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors.
J Biol Chem, 277 (2002), pp. 11019-11025
[17.]
J.R. Schultz, H. Tu, A. Luk, J.J. Repa, J.C. Medina, L. Li, et al.
Role of LXRs in control of lipogenesis.
Genes Dev, 14 (2000), pp. 2831-2838
[18.]
J.J. Repa, G. Liang, J. Ou, Y. Bashmakov, J.M. Lobaccaro, I. Shimomura, et al.
Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta.
Genes Dev, 14 (2000), pp. 2819-2830
[19.]
Y. Zhang, J.J. Repa, K. Gauthier, D.J. Mangelsdorf.
Regulation of lipoprotein lipase by the oxysterol receptors, LXRalpha and LXRbeta.
J Biol Chem, 276 (2001), pp. 43018-43024
[20.]
J.Y. Chiang, R. Kimmel, D. Stroup.
Regulation of cholesterol 7alphahydroxylase gene (CYP7A1) transcription by the liver orphan receptor (LXRalpha).
Gene, 262 (2001), pp. 257-265
[21.]
B.A. Laffitte, J.J. Repa, S.B. Joseph, D.C. Wilpitz, H.R. Kast, D.J. Mangelsdorf, et al.
LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes.
Proc Natl Acad Sci USA, 98 (2001), pp. 507-512
[22.]
P.A. Mak, B.A. Laffitte, C. Desrumaux, S.B. Joseph, L.K. Curtiss, D.J. Mangelsdorf, et al.
Regulated expression of the apolipoprotein E/CI/ C-IV/C-II gene cluster in murine and human macrophages. A critical role for nuclear liver X receptors alpha and beta.
J Biol Chem, 277 (2002), pp. 31900-31908
[23.]
N. Terasaka, A. Hiroshima, A. Ariga, S. Honzumi, T. Koieyama, T. Inaba, et al.
Liver X receptor agonists inhibit tissue factor expression in macrophages.
FEBS J, 272 (2005), pp. 1546-1556
[24.]
R. Walczak, S.B. Joseph, B.A. Laffitte, A. Castrillo, L. Pei, P. Tontonoz.
Transcription of the vascular endothelial growth factor gene in macrophages is regulated by liver X receptors.
J Biol Chem, 279 (2004), pp. 9905-9911
[25.]
K.D. Whitney, M.A. Watson, B. Goodwin, C.M. Galardi, J.M. Maglich, J.G. Wilson, et al.
Liver X receptor (LXR) regulation of the LXRalpha gene in human macrophages.
J Biol Chem, 276 (2001), pp. 43509-43515
[26.]
S.B. Joseph, P. Tontonoz.
LXRs: new therapeutic targets in atherosclerosis?.
Curr Opin Pharmacol, 3 (2003), pp. 192-197
[27.]
B.L. Knight.
ATP-binding cassette transporter A1: regulation of cholesterol efflux.
Biochem Soc Trans, 32 (2004), pp. 124-127
[28.]
J.L. Collins.
Therapeutic opportunities for liver X receptor modulators.
Curr Opin Drug Discov Devel, 7 (2004), pp. 692-702
[29.]
P.H. Groot, N.J. Pearce, J.W. Yates, C. Stocker, C. Sauermelch, C.P. Doe, et al.
Synthetic LXR agonists increase LDL in CETP species.
J Lipid Res, 46 (2005), pp. 2182-2191
[30.]
S.U. Naik, X. Wang, J.S. Da Silva, M. Jaye, C.H. Macphee, M.P. Reilly, et al.
Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo.
Circulation, 113 (2006), pp. 90-97
[31.]
S.B. Joseph, A. Castrillo, B.A. Laffitte, D.J. Mangelsdorf, P. Tontonoz.
Reciprocal regulation of inflammation and lipid metabolism by liver X receptors.
Nat Med, 9 (2003), pp. 213-219
[32.]
D. Ogawa, J.F. Stone, Y. Takata, F. Blaschke, V.H. Chu, D.A. Towler, et al.
Liver x receptor agonists inhibit cytokine-induced osteopontin expression in macrophages through interference with activator protein-1 signaling pathways.
Circ Res, 96 (2005), pp. e59-e67
[33.]
F. Blaschke, O. Leppanen, Y. Takata, E. Caglayan, J. Liu, M.C. Fishbein, et al.
Liver X receptor agonists suppress vascular smooth muscle cell proliferation and inhibit neointima formation in balloon-injured rat carotid arteries.
Circ Res, 95 (2004), pp. e110-e123
[34.]
R. Scalia, D. Pruefer, A.M. Lefer.
A novel lysophosphatidic acid analog, LXR-1035, inhibits leukocyte-endothelium interaction via inhibition of cell adhesion molecules.
J Leukoc Biol, 67 (2000), pp. 26-33
[35.]
M. Albers, B. Blume, T. Schlueter, M.B. Wright, I. Kober, C. Kremoser, et al.
A novel principle for partial agonism of LXR ligands: Competitive recruitment of activators and repressors.
J Biol Chem, 281 (2006), pp. 4920-4930
[36.]
B.M. Forman, E. Goode, J. Chen, A.E. Oro, D.J. Bradley, T. Perlmann, et al.
Identification of a nuclear receptor that is activated by farnesol metabolites.
Cell, 81 (1995), pp. 687-693
[37.]
M. Makishima, A.Y. Okamoto, J.J. Repa, H. Tu, R.M. Learned, A. Luk, et al.
Identification of a nuclear receptor for bile acids.
Science, 284 (1999), pp. 1362-1365
[38.]
D.J. Parks, S.G. Blanchard, R.K. Bledsoe, G. Chandra, T.G. Consler, S.A. Kliewer, et al.
Bile acids: natural ligands for an orphan nuclear receptor.
Science, 284 (1999), pp. 1365-1368
[39.]
W.R. Howard, J.A. Pospisil, E. Njolito, D.J. Noonan.
Catabolites of cholesterol synthesis pathways and forskolin as activators of the farnesoid X-activated nuclear receptor.
Toxicol Appl Pharmacol, 163 (2000), pp. 195-202
[40.]
E.A. Hanniman, G. Lambert, T.C. McCarthy, C.J. Sinal.
Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice.
J Lipid Res, 46 (2005), pp. 2595-2604
[41.]
D.M. Shih, H.R. Kast-Woelbern, J. Wong, Y.R. Xia, P.A. Edwards, A.J. Lusis.
A role for FXR and human FGF-19 in the repression of paraoxonase-1 gene expression by bile acids.
J Lipid Res, 47 (2006), pp. 384-392
[42.]
A. Gutiérrez, E.P. Ratliff, A.M. Andrés, X. Huang, W.L. McKeehan, R.A. Davis.
Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4.
Arterioscler Thromb Vasc Biol, 26 (2006), pp. 301-306
[43.]
D. Bishop-Bailey, D.T. Walsh, T.D. Warner.
Expression and activation of the farnesoid X receptor in the vasculature.
Proc Natl Acad Sci USA, 101 (2004), pp. 3668-3673
[44.]
F. He, J. Li, Y. Mu, R. Kuruba, Z. Ma, A. Wilson, et al.
Downregulation of endothelin-1 by farnesoid X receptor in vascular endothelial cells.
Circ Res, 98 (2006), pp. 192-199
[45.]
M. Downes, M.A. Verdecia, A.J. Roecker, R. Hughes, J.B. Hogenesch, H.R. Kast-Woelbern, et al.
A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR.
Mol Cell, 11 (2003), pp. 1079-1092
[46.]
P. Neuville, Z. Yan, A. Gidlof, M.S. Pepper, G.K. Hansson, G. Gabbiani, et al.
Retinoic acid regulates arterial smooth muscle cell proliferation and phenotypic features in vivo and in vitro through an RARalpha-dependent signalling pathway.
Arterioscler Thromb Vasc Biol, 19 (1999), pp. 1430-1436
[47.]
P. Delerive, D. Monte, G. Dubois, F. Trottein, J. Fruchart-Najib, J. Mariani, et al.
The orphan nuclear receptor RORalpha is a negative regulator of the inflammatory response.
EMBO Rep, 2 (2001), pp. 42-48
[48.]
V. Haxsen, S. Adam-Stitah, E. Ritz, J. Wagner.
Retinoids inhibit the actions of angiotensin II on vascular smooth muscle cells.
Circ Res, 88 (2001), pp. 637-644
[49.]
T. Claudel, M.D. Leibowitz, C. Fievet, A. Tailleux, B. Wagner, J.J. Repa, et al.
Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor.
Proc Natl Acad Sci USA, 27 (2001), pp. 2610-2615
[50.]
A. Aranda, A. Pascual.
Nuclear hormone receptors and gene expression.
Physiol Rev, 81 (2001), pp. 1269-1304
[51.]
T. Deng, S. Shan, Z.B. Li, Z.W. Wu, C.Z. Liao, B. Ko, et al.
A new retinoid-like compound that activates peroxisome proliferator-activated receptors and lowers blood glucose in diabetic mice.
Biol Pharm Bull, 28 (2005), pp. 1192-1196
[52.]
M.D. Leibowitz, R.J. Ardecky, M.F. Boehm, C.L. Broderick, M.A. Carfagna, D.L. Crombie, et al.
Biological characterization of a heterodi-mer-selective retinoid X receptor modulator: potential benefits for the treatment of type 2 diabetes.
Endocrinology, 147 (2006), pp. 1044-1053
[53.]
J. Martínez-González, J. Rius, A. Castelló, C. Cases-Langhoff, L. Badimón.
Neuron-derived orphan receptor-1 (NOR-1) modulates vascular smooth muscle cell proliferation.
Circ Res, 92 (2003), pp. 96-103
[54.]
J. Rius, J. Martínez-González, J. Crespo, L. Badimón.
Involvement of neuron-derived orphan receptor-1 (NOR-1) in LDL-induced mitogenic stimulus in vascular smooth muscle cells: role of CREB.
Arterioscler Thromb Vasc Biol, 24 (2004), pp. 697-702
[55.]
J. Rius, J. Martínez-González, J. Crespo, L. Badimón.
NOR-1 is involved in VEGF-induced endothelial cell growth.
Atherosclerosis, 184 (2006), pp. 276-282
[56.]
J. Crespo, J. Martínez-González, J. Rius, L. Badimón.
Simvastatin inhibits NOR-1 expression induced by hyperlipemia by interfering with CREB activation.
Cardiovasc Res, 67 (2005), pp. 333-341
[57.]
J. Martínez-González, J. Rius, L. Badimón.
A nuclear orphan receptor (NOR-1) identified in human atherosclerotic plaques is expressed by activated monocytes and endothelial cells. Abstractα 072.
J Submcr Cytol Pathol, 32 (2000), pp. 357
[58.]
L. Pei, A. Castrillo, M. Chen, A. Hoffmann, P. Tontonoz.
Induction of NR4A orphan nuclear receptor expression in macrophages in response to inflammatory stimuli.
J Biol Chem, 280 (2005), pp. 29256-29262
[59.]
L. Pei, A. Castrillo, P. Tontonoz.
Regulation of macrophage inflammatory gene expression by the orphan nuclear receptor Nur77.
Mol Endocrinol, (2005, Dec 8),
[Epub ahead of print]
[60.]
H. Li, S.K. Kolluri, J. Gu, M.I. Dawson, X. Cao, P.B. Hobbs, et al.
Cytochrome c release and apoptosis induced by mitochondiral targeting of nuclear orphan receptor TR3.
Science, 289 (2000), pp. 1159-1164
[61.]
S.O. Kim, K. Ono, P.S. Tobias, J. Han.
Orphan nuclear receptor Nur77 is involved in caspase-independent macrophage cell death.
J Exp Med, 197 (2003), pp. 1441-1452
[62.]
H.J. Shin, K.K. Park, B.H. Lee, C.K. Moon, M.O. Lee.
Identification of genes that are induced after cadmium exposure by suppression subtractive hybridization.
Toxicology, 191 (2003), pp. 121-131
[63.]
Z. Wang, G. Benoit, J. Liu, S. Prasad, P. Aarnisalo, X. Liu, et al.
Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors.
Nature, 423 (2003), pp. 555-560
Copyright © 2006. Sociedad Española de Arteriosclerosis y Elsevier España S.L.